JP2009521441A5 - - Google Patents

Claims (64)

A compound represented by:

Where
A represents a 4- to 8-membered heterocyclic ring containing N and Cα,
R ₁ is a C-terminal linked amino acid residue or amino acid analog, or a C-terminal linked peptide, or peptide analog, or

And the bond between R ₁ and N is a thioxamide bond,
R ₂ is missing or represents one or more substituents on the ring A, each of which is independently halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, carboxyl, ester, formate, ketone, Thiocarbonyl, thioester, thioacetate, thioformate, amino, acylamino, amide, nitro, sulfate, sulfonate, sulfonamide, — (CH ₂ ) _m —R ₇ , — (CH ₂ ) _m —OH, — (CH ₂ ) _m -O- lower alkyl, - _{(CH 2)} m -O- lower _{alkenyl, - (CH 2) n -O-} (CH 2) m -R 7, - (CH 2) m -SH, - (CH 2) _m -S- lower alkyl, - _{(CH 2)} m -S- lower alkenyl or _{- (CH 2) n -S- (} CH 2) m -R 7, mackerel , Cyano, isocyanato, thiocyanato, isothiocyanato, cyanato,

Or

And
R ₃ is hydrogen or halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amide, nitro, sulfate, sulfonate, sulfonamide, — (CH ₂ ) _m —R ₇ , — (CH _{2) m -OH, - (CH} 2) m -O- lower alkyl, - _{(CH 2)} m -O- lower _{alkenyl, - (CH 2) n -O-} (CH 2) m -R 7, - ( CH ₂ ) _m —SH, — (CH ₂ ) _m —S-lower alkyl, — (CH ₂ ) _m —S-lower alkenyl or — (CH ₂ ) _n —S— (CH ₂ ) _m —R ₇ , azide , Cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,

Or

Represents
R ₆ is hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, — (CH ₂ ) _m —R ₇ , — (CH ₂ ) _m —OH, — (CH ₂ ) _m —O-alkyl, — (CH ₂ ) _m -O- alkenyl, - _{(CH 2)} m -O- _{alkynyl, - (CH 2) m -O-} (CH 2) m -R 7, - (CH 2) m -SH, - (CH 2) m -S- alkyl, - _{(CH 2)} m -S- alkenyl, - _{(CH 2)} m -S- _{alkynyl, - (CH 2) m -S-} (CH 2) m -R 7,

Represents
R ₇ represents, for each occurrence, substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle,
R ₈ represents hydrogen, —CH ₃ , or — (CH ₂ ) _n —CH ₃ ,
Y ₁ and Y ₂ are independently OH, or a group that can be hydrolyzed to a hydroxyl group, or Y ₁ and Y ₂ are ring structures that can be hydrolyzed to two hydroxyl groups. Linked via a ring having from 5 to 8 atoms,
m is zero or an integer in the range of 1 to 8,
A compound wherein n is an integer in the range of 1 to 8. The compound of claim 1, wherein Y ₁ and Y ₂ are independently OH. The compound is

The compound of claim 2, represented by: R ₂ is present and R ₂ is azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,

Or

The compound according to claim 3, wherein R ₂ is present and R ₂ is azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, or

The compound according to claim 3, wherein R ₂ is present and R ₂ is

The compound according to claim 3, wherein R ₂ is present and R ₂ is

The compound according to claim 3, wherein R ₂ is present and R ₂ is

The compound according to claim 3, wherein R ₁ is

Where
R ₃₆ is lower alkyl or halogen;
R ₃₈ is hydrogen, or R ₃₆ and R ₃₈ together form a 4-7 membered heterocycle containing the N and Cα carbons;
R ₄₀ is, C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino protecting group, the compound according to any one of claims 1 to 8. Or R ₂ is missing, or a lower alkyl or halogen, the compounds according to any one of claims 1 to 9. R ₃ is hydrogen, the compound of any of the preceding claims 1 10.  The compound according to any one of claims 1 to 11, wherein the Cα carbon is substantially present in the R configuration.  13. A compound according to any one of claims 1 to 12, wherein a C? Carbon is substantially present in the S configuration.  14. A compound according to any one of claims 1 to 13, wherein the C [alpha] carbon is present in a racemic mixture of R and S configurations. Y ₁ and _{Y 2} are OH, compounds according to any one of claims 1 to 14. The compound according to any one of claims 1 to 15, wherein R ₁ is a proline, glutamic acid, or alanine residue. The compound according to any one of claims 1 to 16, wherein R ₁ is an alanine residue.

And compounds selected from the above groups, as well as enantiomers, diastereomers, and salts thereof.

Or an enantiomer or diastereomer thereof.

Or an enantiomer or diastereomer thereof.  21. A compound according to any one of claims 1 to 20, wherein the compound is a protease inhibitor.  24. The compound of claim 21, wherein the compound inhibits dipeptidyl peptidase IV with a Ki of 50 nM or less.  23. The compound of claim 22, wherein the compound inhibits dipeptidyl peptidase VIII and IX with a Ki of 100 [mu] M or greater.  24. A compound according to any one of claims 1 to 23, wherein the compound is effective when administered orally. A compound represented by:
Xaa ₁ '-Xaa ₂ ' -Xaa ₁ -Xaa ₂ -W
Where
Xaa ₁ ′, Xaa ₂ ′, and Xaa ₂ each independently represent a naturally occurring amino acid or analog thereof;
Xaa ₁ is a naturally occurring amino acid or analog thereof, Xaa ₁ includes a thioxamide group,
W is -CN, -CH = NR ₅ ,

And
R ₅ is H, alkyl, alkenyl, alkynyl, —C (X ₁ ) (X ₂ ) X ₃ , — (CH ₂ ) _m —R ₆ , — (CH ₂ ) _n —OH, — (CH ₂ ) _n -O- alkyl, - _{(CH 2)} n -O- alkenyl, - _{(CH 2)} n -O- _{alkynyl, - (CH 2) n -O-} (CH 2) m -R 6, - (CH 2) _{n -SH, - (CH 2)} n -S- alkyl, - _{(CH 2)} n -S- alkenyl, - _{(CH 2)} n -S- _{alkynyl, - (CH 2) n -S-} (CH 2) _m— R ₆ , —C (O) C (O) NH ₂ , or —C (O) C (O) OR ₇ ;
R ₆ independently represents, for each occurrence, substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle,
R ₇ independently represents for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle,
Y ₁ and Y ₂ can be independently or together OH, or a group that can be hydrolyzed to a hydroxyl group, including cyclic derivatives, and Y ₁ and Y ₂ can be from 5 to 5 in the ring structure. Linked through a ring having up to 8 atoms,
R ₅₀ represents O or S;
R ₅₁ represents N ₃ , SH, NH ₂ , NO ₂ , or —OR ₇ ,
R ₅₂ represents hydrogen, lower alkyl, amine, —OR ₇ , or a pharmaceutically acceptable salt, or
R ₅₁ and R ₅₂ together with the phosphorus atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
X ₁ represents halogen,
X ₂ and X ₃ each represent hydrogen or halogen;
m is 0 or an integer in the range of 1 to 8,
A compound wherein n is an integer in the range of 1 to 8. A compound represented by:

Where
A represents a 4-8 membered heterocyclic ring containing N and Cα carbons;
W is -CN, -CH = NR ₅ ,

Represents
R ₁ represents a C-terminal binding peptide or peptide analog that is a substrate for an activating enzyme;
R ₂ is missing or represents one or more substituents on the ring A, each independently halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amide, Nitro, sulfate, sulfonate, sulfonamide, — (CH ₂ ) _m —R ₆ , — (CH ₂ ) _m —OH, — (CH ₂ ) _m —O-lower alkyl, — (CH ₂ ) _m —O-lower Alkenyl, — (CH ₂ ) _n —O— (CH ₂ ) _m —R ₆ , — (CH ₂ ) _m —SH, — (CH ₂ ) _m —S-lower alkyl, — (CH ₂ ) _m —S— Lower alkenyl or — (CH ₂ ) _n —S— (CH ₂ ) _m —R ₆ , azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,

Or

And
R ₃ represents hydrogen or lower alkyl,
R ₄ represents hydrogen, halogen, lower alkyl, lower alkenyl, or lower alkynyl,
R ₅ is, independently of each occurrence, H, alkyl, alkenyl, alkynyl, —C (X ₁ ) (X ₂ ) X ₃ , — (CH ₂ ) _m —R ₆ , — (CH ₂ ) _n — OH, — (CH ₂ ) _n —O-alkyl, — (CH ₂ ) _n —O-alkenyl, — (CH ₂ ) _n —O-alkynyl, — (CH ₂ ) _n —O— (CH ₂ ) _m — R ₆ , — (CH ₂ ) _n —SH, — (CH ₂ ) _n —S-alkyl, — (CH ₂ ) _n —S-alkenyl, — (CH ₂ ) _n —S-alkynyl, — (CH ₂ ) _n —S— (CH ₂ ) _m —R ₆ , —C (O) C (O) NH ₂ , or —C (O) C (O) OR ₇ ;
R ₆ independently represents, for each occurrence, substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
R ₇ independently represents for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle,
R ₈ represents hydrogen, —CH ₃ , or — (CH ₂ ) _n —CH ₃ ,
Y ₁ and Y ₂ can be independently or together OH, or a group that can be hydrolyzed to a hydroxyl group, including cyclic derivatives, and Y ₁ and Y ₂ can be from 5 to 8 in the ring structure. Linked through a ring having up to
R ₅₀ represents O or S;
R ₅₁ represents N ₃ , SH, NH ₂ , NO ₂ , or —OR ₇ ,
R ₅₂ represents hydrogen, lower alkyl, amine, —OR ₇ , or a pharmaceutically acceptable salt, or R ₅₁ and R ₅₂ together with the phosphorus atom to which they are attached, 5 to 8 in said ring structure Complete a heterocyclic ring with the atoms
X ₁ represents halogen,
X ₂ and X ₃ each represent hydrogen or halogen;
m is zero or an integer in the range of 1 to 8,
A compound wherein N is an integer in the range of 1-8.   27. A compound according to claim 26, wherein A represents a 5-membered heterocycle comprising the N and the C [alpha] carbon. 28. A compound according to claim 26 or 27, wherein W is -B (Y < ₁ >) (Y < ₂ >). Or R ₂ is missing, a halogen or a lower alkyl, any one compound as claimed in claim 26 28. R ₄ represents hydrogen or lower alkyl, any one compound as claimed in claim 26 29. R ₅ represents H or alkyl, a compound of any one of claims 26 30. Y ₁ and _{Y 2} are OH, any one compound as claimed in claim 26 31. 32. A compound according to any one of claims 26 to 31 wherein W is -B (OH) ₂ . The compound is

27. The compound of claim 26, represented by: R ₂ is missing, or halogen, lower alkyl, azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,

Or

35. The compound of claim 34, wherein R ₄ represents hydrogen or lower alkyl, A compound according to claim 34. R ₂ is present and R ₂ is azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,

Or

35. The compound of claim 34, wherein R ₂ is present and R ₂ is azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, or

35. The compound of claim 34, wherein R ₂ is present and R ₂ is

35. The compound of claim 34, wherein R ₂ is present and R ₂ is

Or

35. The compound of claim 34, wherein The compound is

27. The compound of claim 26, represented by: R ₂ is hydrogen, halogen, lower alkyl, azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,

Or

42. The compound of claim 41, wherein R ₄ represents hydrogen or lower alkyl, A compound according to claim 41. R ₂ is azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,

Or

42. The compound of claim 41, wherein R ₂ is azide, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, or

42. The compound of claim 41, wherein R ₂ is

42. The compound of claim 41, wherein R ₂ is

Or

42. The compound of claim 41, wherein R ₁ is

48. The compound of any one of claims 26 to 47, wherein:   49. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof. 49. A method for inhibiting the proteolytic activity of an enzyme in vitro, the method comprising contacting the compound according to any one of claims 1 to 48 with a post-proline cleaving enzyme in vitro .   51. The method of claim 50, wherein the enzyme is mammalian dipeptidyl peptidase IV (DPP IV). 49. A composition for suppressing the proteolytic activity of a postproline cleaving enzyme in a patient, comprising the compound according to any one of claims 1 to 48. 53. The composition of claim 52, wherein the composition increases the plasma concentration of a peptide hormone selected from the group consisting of glucagon-like peptide, NPY, PPY, secretin, GLP-1, GLP-2, and GIP. 49. A composition for controlling glucose metabolism in a patient, comprising a compound according to any one of claims 1 to 48. The patient is suffering from type 2 diabetes, insulin resistance, impaired glucose tolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 54. The composition according to 54. 56. The composition of claim 54 or 55, used in combination with insulin, an insulin secretagogue, or both. 57. Any of claims 54 to 56, used in combination with an M1 receptor antagonist, a prolactin inhibitor, an agent that acts on an ATP-dependent potassium channel in beta cells, metformin, a glucosidase inhibitor, or any combination thereof . A composition according to claim 1. 49. A method for inhibiting proteasome, DP8, DP9, or prostate-specific antigen proteolytic activity in vitro, wherein the compound according to any one of claims 1 to 48 is added to the proteasome, DP8, DP9, or prostate-specific antigen. A method comprising the step of contacting in vitro . Containing a compound according to any one of claims 1 48, the patient's proteasome, DP8, DP9, or prostate specific composition for inhibiting the proteolytic activity of the antigen.   49. A packaged medicament comprising the compound of any one of claims 1 to 48 and instructions for its use.   61. The packaged pharmaceutical product of claim 60, wherein the instructions relate to use in controlling glucose metabolism or inhibiting postproline cleaving enzyme.   61. The packaged pharmaceutical product of claim 60, wherein the instructions relate to use in the suppression of proteasome, DP8, DP9, or prostate specific antigen.   61. The packaged medicament of claim 60, wherein the compound is formulated concurrently with or packaged together with insulin, an insulin secretagogue, or both.   The compound is formulated at the same time or packaged together with an M1 receptor antagonist, a prolactin inhibitor, an agent that acts on an ATP-dependent potassium channel in beta cells, metformin, a glucosidase inhibitor, or any combination thereof. 61. The packaged pharmaceutical product of claim 60.